The rat has been of limited use for studying starvation in man because it survives for only a short time and it does not conserve protein. Preliminary studies from this laboratory indicate that both of these difficulties can be obviated by using a rat made obese by feeding a high fat diet. We propose to evaluate the obese rat as a model for studying starvation in man with the aim of determining how the utilization of "fat" leads to protein conservation during fasting. Initially we will compare the metabolic response to starvation of obese rats and appropriate controls to that of man. Changes in body composition, the concentrations of hormones, metabolites and amino acids in blood and the excretion of nitrogenous products and ketone bodies in urine will be noted after variable periods of starvation. In addition, we will determine arterio-venous differences for various substrates across muscle and brain. To study the basis for metabolic alterations in individual tissues, we will assess changes in key regulatory enzymes, metabolites and cofactors in skeletal muscle, brain, heart, liver and kidney. Protein catabolism in skeletal muscle will be assessed from the excretion of 3-methylhistidine in urine, from measurements of arterio-venous differences for amino acids across the hindquarter of an intact rat, and from determinations of protein synthesis and proteolysis utilizing the isolated perfused rat hindquarter. To study the effect of lipid substrates on protein catabolism, we will determine the influence of perfusion with fatty acids, acetoacetate and inhibitors of fatty acid metabolism on protein metabolism in the isolated hindquarter. Similar studies will be carried out with soleus and extensor digitorum longus muscle preparations to distinguish differences between red and white skeletal muscle. Finally, in non-obese fasting rats, we will determine the effect of feeding pure fat on protein conservation, using the approach described above.